Paracetamol glutathione conjugates

Side-effects are rare and may include hematological reactions, leucopenia, agranulocytosis and other hypersensitivity reactions. Paracetamol has a narrow therapeutic dose range and overdosage induces severe liver and renal damage (Lewis and Paloucek, 1991) via accumulation of a toxic metabolite, N- acetyl-benzoquinoneimine (NABQI). Acetylcysteine or methionine, which increase glutathione conjugation of the metabolite, are used as the antidote. 

Disposition in the Body. Readily absorbed after oral administration, but subject to extensive first-pass metabolism. It is metabolised mainly in the liver by O-dealkylation to paracetamol and acetaldehyde, followed by conjugation of the paracetamol with sulphate or glucuronic acid (see under Paracetamol) other reactions are deacetylation to phenetidine (/7-ethoxyaniline), N-,2-, and a-hydroxylation forming mainly 2-hydroxyphenet-idine and also 2-hydroxyphenacetin, sulphate conjugation of de-acetylated metabolites, and glutathione conjugation to form... 

Glutathione contains a nucleophilic -SB group which In many cases detoxifies electrophilic reactive Intermediates through formation of stable glutathione conjugates, as In the case of paracetamol. 

These have been reviewed in SED VIII (p. 188) and recent literature has added to our knowledge of the topic (243, 244, 221 ). As expected, the biliary secretion of bromsulphthalein is reduced in patients taking hepatotoxic doses of paracetamol. A similar but less marked effect is apparent even after therapeutic doses and paracetamol competes with bromsulphthalein for hepatic uptake, glutathione conjugation and biliary excretion (245 ). 

Figure 7.10 Metabolism of paracetamol. With therapeutic doses, paracetamol is metabolised to the glucuronide and sulphate conjugates. With higher doses these pathways become saturated and metabolism proceeds via die P-450-mediated route, with the formation of the toxic metabolite benzoquinone. This is normally metabolised by conjugation with glutathione. When glutathione is depleted benzoquinone is free to interact with cellular macromolecules, leading to cellular damage.

Figure 7.19 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate /V-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins. Alternatively, NAPQI can be reduced back to paracetamol by glutathione, forming oxidized glutathione (GSSG).

Paracetamol is metabolised in the liver, where it is converted to a highly toxic intermediate that is normally detoxified by conjugation with glutathione. In overdose, this detoxification mechanism is overwhelmed and the free toxic metabolite causes hepatitis and necrosis, which can prove fatal. 

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